The effect of beta-interferon therapy on myelin basic protein-elicited CD4+ T cell proliferation and cytokine production in multiple sclerosis

Interferon (IFN)-beta therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-beta therapy. The MBP-elicited IFN-gamma-, TNF-alpha- and IL-10 production decreased during therapy (p<0.007-0.03), while the IL-6 production increased (p<0.03). No significant change was observed in the MBP-induced CD4+ T cell proliferation, or in the production of IL-4, IL-5 and brain-derived neurotrophic factor. In comparison, IFN-beta therapy reduced IFN-gamma and IL-4 responses to TT (p<0.003 and p<0.04). Thus, IFN-beta inhibits IFN-gamma production in general, presumably alleviating the detrimental influence of IFN-gamma in MS. However, the increase in proinflammatory IL-6 and the decrease in anti-inflammatory IL-10 responses suggest that IFN-beta has more diverse effects than previously assumed.     

Monocyte-derived cytokines in multiple sclerosis

MS is an inflammatory, presumably autoimmune, disease mediated by the activation of T cells, B cells and monocytes (MO). Inflammation is thought to occur early during the relapsing-remitting phase of MS (RRMS), whereas in the later phases of MS such as secondary progressive MS (SPMS), inflammation tends to diminish. Our objective was to compare the types and amounts of proinflammatory and regulatory cytokines produced by MO from relapsing-remitting patients with or without treatment with IFN-beta (RRMS+ therapy, RRMS- therapy), respectively, from secondary progressive patients (SPMS) and from healthy controls (HC). MO were isolated by a density-gradient technique and three different techniques (RNase protection assay, ELISA and intracellular cytokine staining) were used to assess cytokine levels. An increase in IL6, IL12 and TNF-alpha was observed by all three methods for RRMS- therapy and for SPMS patients compared to HC and RRMS+ therapy patients. We conclude that proinflammatory and regulatory monokines can be derived from MO of MS patients and that these levels are modulated by IFN-beta therapy. Although it is believed that inflammation tends to diminish in SPMS patients, our data show that inflammatory cytokines continue to be released at high levels, suggesting that IFN-beta or IL10 treatment may be beneficial for this group.     

Multiple sclerosis is associated with an imbalance between tumour necrosis factor-alpha (TNF-alpha)- and IL-10-secreting blood cells that is corrected by interferon-beta (IFN-beta) treatment

The up-regulated B cell responses detectable in cerebrospinal fluid (CSF) and the augmented myelin antigen-specific T cell responses observed in the CSF as well as systematically in patients with multiple sclerosis (MS) suggest the involvement of cytokines in disease development and perpetuation. Here we report on the parallel involvement of TNF-alpha, IL-6, IFN-gamma and IL-10 in MS and controls, using enzyme-linked immunospot (ELISPOT) assays to detect and enumerate cytokine-secreting mononuclear cells (MNC) prepared from blood and, for IL-6 and IL-10, from CSF without in vitro stimulation. MS is associated with elevated levels of TNF-alpha-secreting blood MNC when compared with levels in groups of control patients with myasthenia gravis (MG) and other neurological diseases (OND) or healthy subjects. This elevation was confined to patients with untreated MS and not present in those examined during ongoing treatment with IFN-beta. Untreated patients with MS had lower numbers of IL-10-secreting blood MNC compared with the three control groups. In patients undergoing treatment with IFN-beta, numbers of IL-10-secreting cells were in the same range as in controls. Normalization of TNF-alpha from elevated, and of IL-10 from decreased levels could be one reason for the beneficial effects of IFN-beta in MS, although it remains to be shown whether these changes reflect phenomena primarily involved in MS pathogenesis or secondary changes. In CSF, levels of IL-10-secreting cells were higher than in blood in both MS and OND, with no difference between these groups. Systemic aberrations of IL-6 and IFN-gamma and of IL-6 in CSF in MS versus controls were only minor, irrespective of treatment with IFN-beta.     

Serum concentrations of cytokines in patients with active tuberculosis (TB) and after treatment

During TB cytokines play a role in host defence. To determine the cytokine pattern during various disease stages of TB, serum levels of IL-12, interferon-gamma (IFN-γ), IL-4, IL-6 and IL-10 were measured in 81 patients with active TB, 15 patients during therapy and 26 patients after anti-tuberculous therapy as well as in 16 persons who had been in close contact with smear-positive TB and in 17 healthy controls. IFN-γ was elevated during active TB when compared with healthy controls, declining during and after treatment. IL-12 (p40 and p70) serum levels were not significantly higher in patients with active TB compared with any of the other groups. IL-4 levels were low in all groups. IL-6 and IL-10 serum levels were elevated in patients with active TB and during treatment. In patients with active TB serum levels of IFN-γ and IL-6 were higher in patients with fever, anorexia and malaise. IL-12 levels were higher in patients with a positive smear. Cytokine levels did not correlate with localization of TB (pulmonary versus extrapulmonary), or skin test positivity. Cytokines directing a Th1 response (IL-12) or a Th2 response (IL-4) were not elevated in sera of this large group of patients with pulmonary and extrapulmonary TB. In patients with active TB, cytokines that were elevated in serum were IFN-γ, IL-6 and IL-10.     

Regulation by IFN-beta of inducible nitric oxide synthase and interleukin-12/p40 in murine macrophages cultured in the presence of Chlamydia pneumoniae antigens.

Chlamydia pneumoniae has been demonstrated in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS). Interferon-beta (IFN-beta) has favorable effects on the clinical course of MS. We investigated whether the beneficial effects of IFN-beta in MS may involve its role in regulating nitric oxide (NO) and interleukin-12 (IL-12) in macrophages, as these immune modulators form part of the innate immune response to intracellular pathogens, such as C. pneumoniae. Murine macrophages in cultures exposed to elementary body antigens or recombinant major outer membrane protein (rMOMP) of C. pneumoniae demonstrate a significant increase in NO as well as production of IL-12/p40 in culture supernatants compared with basal levels. Addition of murine IFN-beta increased NO activity in murine macrophages cultured with chlamydial antigens. Addition of neutralizing anti-IFN-beta antibody prevented the NO increase. In contrast to its effect on inducible NO synthase (iNOS), IFN-beta reduced induction of IL-12/p40 following culture with either elementary body antigens or rMOMP. Inhibition was reversed with anti-IFN-beta antibody. If C. pneumoniae infection is responsible for the inflammatory response in the pathogenesis of MS, the beneficial effects of IFN-beta in MS may be due to its enhancing intracellular NO activity while inhibiting secretion of the proinflammatory cytokine, IL-12.     

慢性丙型肝炎患者血清细胞因子水平的变化及意义

目的:检测慢性丙型肝炎患者血清细胞因子IL-2、IFN-г、IL-5、IL-6、IL-12P70和P40水平,探讨其与患者血清ALT水平、HVC RNA载量、HCV基因型及干扰素疗效的关系。方法:检测30例健康对照者和30例慢性丙型肝炎患者干扰素治疗前后血清IL-2、IFN-г、IL-5、IL-6、IL-12P70和P40的含量,比较干扰素治疗应答组和无应答组之间细胞因子水平的差异及上述细胞因子水平与血清ALT水平、HCV基因型、HCVRNA载量等的关系。血清细胞因子检测应用ELISA法,HCV基因分型应用直接测序法,HCVRNA载量采用荧光定量PCR法。结果:与健康对照组相比,慢性丙型肝炎患者血清IL-2含量明显降低,IL-5和IL-12P40明显生高;血清IL-6含量与血清ALT水平呈正相关,与RNA载量呈负相关;HCV基因型1型患者血清IL-6含量明显高于2型,其他基因型和亚型之间细胞因子水平均无显著性差异;干扰素治疗的持续应答率为46.7%,应答组和无应答组治疗前血清细胞因子水平均无显著性差异,但应答组治疗结束时IFN-γ含量较治疗前明显升高。结论:血清Th1/Th2细胞因子水平失衡与丙型肝炎的慢性化和肝脏炎症活动相关;干扰素治疗前血清Th1/Th2细胞因子水平与干扰素治疗效果无关,不能对疗效进行预测,干扰素诱导的Th1细胞优势反应与持续应答有关。     

Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-beta and IL-10.

Multiple sclerosis (MS) is assumed to result from autoaggressive T cell-mediated immune responses, in which T helper type 1 (Th1) cells producing cytokines, e.g. IFN-gamma and lymphotoxin promote damage of oligodendrocyte-myelin units. Dendritic cells (DCs) as potent antigen presenting cells initiate and orchestrate immune responses. Whether phenotype and function of DCs with respect to Th1 cell promotion are altered in MS, are not known. This study revealed that blood-derived DCs from MS patients expressed low levels of the costimulatory molecule CD86. In addition, production of IFN-gamma by blood mononuclear cells (MNCs) was strongly enhanced by DCs derived from MS patients. IFN-beta and IL-10 inhibited the costimulatory capacity of DCs in mixed lymphocyte reaction (MLR) and showed additive effects on suppression of IL-12 production by DCs. Correspondingly, DCs pretreated with IFN-beta and IL-10 significantly suppressed IFN-gamma production by MNCs. IFN-beta in vitro also upregulated CD80 and, in particular, CD86 expression on DCs. In vitro, anti-CD80 antibody remarkably increased, while anti-CD86 antibody inhibited DC-induced IL-4 production in MLR. We conclude that DC phenotype and function are altered in MS, implying Th1-biased responses with enhanced capacity to induce Th1 cytokine production. In vitro modification of MS patients' DCs by IFN-beta and IL-10 could represent a novel way of immunomodulation and of possible usefulness for future immunotherapy of MS.     

IL-18和IL-10在慢性丙型肝炎抗病毒疗效中的早期预测作用

目的观察慢性丙型肝炎患者干扰素联合利巴韦林治疗过程中血清白细胞介素-18（IL-18）和白细胞介素-10（IL-10）水平的变化,探讨它们在慢性丙型肝炎抗病毒疗效中的早期预测作用。方法采用酶联免疫吸附法（ELISA）检测30例正常人．82例慢性丙型肝炎患者抗病毒治疗前、治疗4周、治疗24周血清中IL-18和IL-10的水平．同时检测肝功能和HCVRNA（定量PCR法）。结果慢性丙型肝炎患者治疗前血清IL-18和IL-10的水平显著高于正常人（P〈0．01）,其值与谷丙转氨酶（ALT）活性呈显著正相关。抗病毒有效者,在不同时间点血清IL-18和IL—10的水平均较治疗前显著下降（P〈0．05）,其中,完全应答组细胞因子水平治疗前后改变更显著．而无效者改变不明显。结论IL-18和IL-10在慢性丙型肝炎发病中起一定作用,早期检测IL—18和IL-10的水平对干扰素联合利巴韦林抗病毒的疗效预测有重要意义。     

Influence of different dosage schedules of inhaled fluticasone propionate on peripheral blood cytokine concentrations in childhood asthma

BACKGROUND: Asthma is characterized by eosinophilic airways inflammation with elevated levels of IL-4, IL-5 and sICAM-1, and reduced levels of IL-10 and IFN-gamma. Inhaled corticosteroids powerfully reduce airways inflammation. OBJECTIVE: To investigate if eosinophil counts, serum eosinophilic cationic protein (ECP) and sICAM-1 levels, as well as serum and production of cytokines (IL-4, IL-5, IL-10, IFN-gamma) by peripheral blood monocytes (PBMCs) are useful markers to monitor therapy with inhaled fluticasone propionate (FP) in asthmatic children. METHODS: In a double-blind, 1-year study, 55 asthmatic children (aged 6-10 years) stopped inhaled corticosteroids for a mean period of 24 days and were randomized to receive either FP 200 microg/day (constant dose group), or a starting dose of FP 1000 microg/day with two monthly reductions to 500, 200 and 100 microg/day (stepdown group). Hyper-responsiveness, symptom scores and blood sampling were performed at 2-month intervals. RESULTS: Symptoms and hyper-responsiveness improved significantly in both treatment groups after reintroduction of FP. Eosinophil counts decreased significantly more during the first 2 months of FP in the stepdown group than in the constant dose group (P = 0.03). We found a trend towards a dose-dependent response in changes of eosinophil counts and serum ECP levels during treatment. Serum IL-4 and IL-5 levels were undetectable in the majority of children. No significant effect of the dose of FP on the release of IL-4, IL-5, IL-10 or IFN-gamma by Con A stimulated PBMCs was found. sICAM-1 levels did not significantly differ at any time point between the two groups. CONCLUSION: Serum ECP as well as peripheral blood eosinophils, cytokine production by PBMCs and sICAM-1 levels are insensitive markers in titrating and monitoring therapy with inhaled corticosteroids over a wide dose range in childhood asthma.     

Discordant effect of IFN-beta1a therapy on anti-IFN antibodies and thyroid disease development in patients with multiple sclerosis.

Interferon-beta1b (IFN-beta1b) therapy is associated with a relatively high risk of developing thyroid disease. IFN-beta1a is regarded as less immunogenic than IFN-beta1b because of its structural homology to natural IFN-beta. We assessed the effect of 1 year of IFN-beta1a treatment on thyroid function and autoimmunity in 14 multiple sclerosis (MS) patients. The results were compared with those obtained in a series of 31 MS patients treated with IFN-beta1b. The prevalence of positive binding antibody (BAb) titer and neutralizing (NAb) anti-IFN antibody titer in the two groups was also assessed. The BAb and NAb positivity rate in IFN-beta1a-treated patients was significantly lower than in the group submitted to IFN-beta1b therapy (7% vs. 84% and 0% vs. 30%, respectively). Although the incidence of thyroid dysfunction was slightly higher in IFN-beta1b-treated patients than in those undergoing IFN-beta1a treatment (33% vs. 23%, respectively), it did not reach statistical significance. Thyroid disease was unrelated to the presence of positive serum BAb or NAb titer in both the group undergoing IFN-beta1a therapy and in that treated with IFN-beta1b. In both groups, thyroid disease developed mostly in women (71%) against a background of preexisting thyroiditis and a diffuse hypoechoic ultrasound thyroid pattern (80%). IFN-beta1a treatment was associated with a significantly lower prevalence of both BAb and NAb-positive titers than was IFN-beta1b. Conversely, thyroid disease was similar and unrelated to the presence of positive anti-IFN-beta antibody titer. Therefore, routine thyroid assessment may be advised during IFN-beta1a treatment, especially in patients with preexisting thyroiditis.     

The antiinflammatory cytokine interleukin-13 is not detectable in the circulation of multiple sclerosis patients and is not inducible by interferon-beta1b treatment, that neither modifies its ex vivo secretion from peripheral blood mononuclear cells

Interleukin (IL)-13 is a T-cell derived cytokine closely related to IL-4 that possesses powerful antiinflammatory properties. In this study we have evaluated the blood levels of IL-13 in patients with multiple sclerosis (MS), either with relapsing remitting or secondary chronic progressive (CP) course of the disease, and have also examined the effect of treatment with interferon (IFN)-beta 1b given on alternate days for 10 days both on the serum levels of IL-13 and on the ex vivo secretory capacity of mononuclear cells from MS patients. IL-13 was not detectable in the circulation of MS patients regardless of whether RR MS patients with stable or active disease or those suffering from secondary CP MS were studied. Moreover, circulating levels of IL-13 were not induced by treatment with IFN- beta1b, that was neither capable of modifying the ex vivo IL-13 secretory capacity of peripheral blood mononuclear cells. These data neither anticipate a role for endogenous IL-13 in down-regulating immunoinflammation during MS attacks nor suggest that IFN-betalb treatment exerts its favourable effects on the course of RR MS by augmenting the secretion of this antiinflammatory cytokine.     

Decreased serum levels of sCD40L and IL-31 correlate in treated patients with Relapsing-Remitting Multiple Sclerosis

The CD40/CD40L system is a binding key for co-stimulation of immune cells. Soluble form of CD40L has been widely studied as marker of inflammatory and autoimmune diseases. Here we analyze serum concentrations of sCD40L, as well as 14 cytokines, in patients with Multiple Sclerosis (MS) treated with Glatiramer acetate or Interferon beta. In the healthy control group, we found in serum a highly positive correlation between sCD40L and Interleukin (IL)-31, an anti-inflammatory Th2 cytokine. Additionally, an important reduction in IL-31 and sCD40L serum levels, as well as a significant reduction in CD40 mRNA expression and complete depletion of CD40L mRNA, detected from peripheral blood cells, was found in treated patients with MS. Therefore, sCD40L and IL-31 must be taken into account as possible prognostic markers when analyzing the disease progress of MS in order to provide more personalized treatment.     

Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation

Putative markers of inflammation such as serum beta2-microglobulin and neopterin have been shown to be transiently upregulated following interferon-beta (IFN-beta) administration to multiple sclerosis (MS) patients. However, to date the role of the important inflammatory mediators serum amyloid A protein (SAA) and C-reactive protein (CRP) have not been described. Here we show that SAA but not CRP is elevated in relapsing-remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-beta1a (Avonex). This pattern of expression was found to parallel that of beta2-microglobulin and neopterin following injection and was mirrored by a selective activation of peripheral monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86). Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated. Following IFN-beta1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients. In addition, IFN-beta1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.     

Dynamics of hepatitis C virus monitored by real-time quantitative polymerase chain reaction during first 2 weeks of IFN-beta treatment are predictive of long-term therapeutic response.

The relation between the change in hepatitis C virus (HCV) RNA levels at the start of interferon-beta (IFN-beta) treatment and the long-term therapeutic response remains poorly defined. In 20 patients with chronic hepatitis C who received IFN-beta (total dose 126-756 MU), the changes in serum HCV RNA during the first 2 weeks of therapy were monitored by real-time quantitative polymerase chain reaction (PCR). The serum HCV RNA level decreased rapidly during the first 24 h of therapy (first phase) and more slowly thereafter (second phase), with a mean exponential decay rate of 1.17 log10/day and 0.37 log10/day, respectively. Three patients had a sustained virologic response, 10 patients had a transient response, and 7 patients had no response. The differences in the rate of first-phase viral decline among the three groups were not significant (p = 0.21), but the differences in the rate of second-phase viral decline were significant (p = 0.0021). The mean decay rate between the end of the first 24 h and day 14 was 0.96 +/- 0.43 log10/day in sustained responders, 0.39 +/- 0.30 log10/day in transient responders, and 0.13 +/- 0.09 log10/day in nonresponders. We conclude that during the first 2 weeks of therapy, changes in serum HCV RNA levels as monitored by real-time quantitative PCR can be used to predict the long-term response to treatment with IFN-beta.     

Correlation of serum IL-13 and IL-5 levels with clinical response to Glatiramer acetate in patients with multiple sclerosis

Glatiramer acetate (GA) is effective in the treatment of Multiple Sclerosis (MS) presumably by the induction of an immunoregulatory T-cell response. We have previously shown that GA directly induces the Th2 cytokines IL-13 and IL-5 in T-cells in vitro. In the present study we compared the in vitro response to GA in healthy controls, untreated and GA-treated MS patients and tested whether the induction of IL-13 and IL-5 secretion is also detectable in the serum of 25 MS patients treated with GA. Patients were grouped into clinical responders and nonresponders in order to determine a possible correlation with the immunological response. As a result we found a significant increase of IL-13 in the serum of clinical GA-responders whereas IL-13 was not detectable in controls, untreated MS (P < 0.001) and nonresponders (P = 0.015). Similarly, GA-treatment increased serum levels of IL-5 (P = 0.001). The correlation of serum IL-5 and clinical response was also significant (P = 0.039), however, there was an overlap between the different groups. The selective induction of IL-13 and IL-5 but not IL-4 by GA treatment suggests that the specific biological functions of these cytokines might be important for the therapeutic mechanism of GA. Measurement of serum IL-13 and IL-5 levels is a simple and inexpensive tool for monitoring the response to GA in MS patients.     

Measured neutralizing titers of IFN-beta neutralizing antibodies (NAbs) can depend on the preparations of IFN-beta used in the assay.

An immune response to recombinant human protein therapeutics, including type I interferons (IFNs), has the potential to have a serious negative impact on safety and efficacy. Monitoring of patients for neutralizing antibodies (NAbs) often is advisable. In the case of IFN-beta therapy for multiple sclerosis (MS), we obtained reproducible quantitative titers of NAbs using an improved and well-characterized assay based on a 10-fold reduction of a challenge dose of IFN-beta. However, the observed titer was significantly affected by the preparation of IFN-beta used as the assay challenge. NAb titers obtained using IFN-beta1b averaged 3-5-fold lower than titers of the same sample assayed using either IFN-beta1a or human fibroblast-derived IFN-beta. This was the case whether neutralizing serum was obtained from patients on therapy with IFN-beta1a or IFN-beta1b. The reason for this apparent titer difference is not fully understood but appears to be related to protein folding or other structural properties that differentiate the IFN-beta1b both from commercial IFN-beta1a preparations and from human fibroblast-derived IFN-beta.     

Innate immunity modulates autoimmunity: type 1 interferon-beta treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation

Type 1 interferon-beta (T1IFN-beta) is an innate cytokine and the first-choice therapy for multiple sclerosis (MS). It is still unclear how T1IFN-beta, whose main function is to promote innate immunity during infections, plays a beneficial role in autoimmune disease. Here we show that T1IFN-beta promoted the expansion and function of invariant natural killer (iNKT) cells, an innate T-cell subset with strong immune regulatory properties that is able to prevent autoimmune disease in pre-clinical models of MS and type 1 diabetes. Specifically, we observed that T1IFN-beta treatment significantly increased the percentages of Valpha24(+) NKT cells in peripheral blood mononuclear cells of MS patients. Furthermore, iNKT cells of T1IFN-beta-treated individuals showed a dramatically improved secretion of cytokines (interleukins 4 and 5 and interferon-gamma) in response to antigenic stimulation compared to iNKT cells isolated from the same patients before T1IFN-beta treatment. The effect of T1IFN-beta on iNKT cells was mediated through the modulation of myeloid dendritic cells (DCs). In fact, DCs modulated in vivo or in vitro by T1IFN-beta were more efficient antigen-presenting cells for iNKT cells. Such a modulatory effect of T1IFN-beta was associated with up-regulation on DCs of key costimulatory molecules for iNKT (i.e. CD80, CD40 and CD1d). Our data identified the iNKT cell/DC pathway as a new target for the immune regulatory effect of T1IFNs in autoimmune diseases and provide a possible mechanism to explain the clinical efficacy of T1IFN-beta in MS.     

Interferon-beta therapy reduces CD4+ and CD8+ T-cell reactivity in multiple sclerosis

Therapy with interferon-beta (IFN-beta) has well-established clinical effects in multiple sclerosis (MS), albeit the immunomodulatory mechanisms are not fully understood. We assessed the prevalence and functional capacity of CD4+ and CD8+ T cells in healthy donors, and in untreated and IFN-beta-treated MS patients, in response to myelin oligodendrocyte glycoprotein (MOG). The proportion of CD45RO+ memory T cells was higher in MS patients than in healthy donors, but returned to normal values upon therapy with IFN-beta. While CD45RO+ CD4+ T cells from all three groups responded to MOG in vitro, untreated patients showed augmented proliferative responses compared to healthy individuals and IFN-beta treatment reduced this elevated reactivity back to the values observed in healthy donors. Similarly, the response of CD45RO+ CD8+ T cells to MOG was strongest in untreated patients and decreased to normal values upon immunotherapy. Overall, the frequency of peripheral CD45RO+ memory T cells ex vivo correlated with the strength of the cellular in vitro response to MOG in untreated patients but not in healthy donors or IFN-beta-treated patients. Compared with healthy individuals, responding CD4+ and CD8+ cells were skewed towards a type 1 cytokine phenotype in untreated patients, but towards a type 2 phenotype under IFN-beta therapy. Our data suggest that the beneficial effect of IFN-beta in MS might be the result of the suppression or depletion of autoreactive, pro-inflammatory memory T cells in the periphery. Assessment of T-cell subsets and their reactivity to MOG may represent an important diagnostic tool for monitoring successful immunotherapy in MS.     

Systemic inflammatory responses in children with acute otitis media due to Streptococcus pneumoniae and the impact of treatment with clarithromycin

This pilot study was designed to determine the serum cytokine profile of acute otitis media (AOM) due to Streptococcus pneumoniae and the impact of clarithromycin (Abbott Laboratories, Inc). Serum levels of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), IL-6, and IL-8 were measured at diagnosis and 3 to 5 days after start of antibiotic treatment in 10 patients (mean age, 18.3 +/- 13.9 months) who had middle ear fluid culture positive for S. pneumoniae. The mean concentrations of all cytokines were elevated at diagnosis of AOM compared to levels in healthy controls, yet only IL-6 reached statistical significance (P = 0.05). IL-6 showed a statistically significant decrease in mean serum concentration at visit 2 (P = 0.03). IL-8 displayed a similar pattern to IL-6, but the difference between samples from day 1 and day 2 did not reach statistical significance. The cytokines IL-1 beta and TNF-alpha appear to be elevated in the serum of patients with S. pneumoniae AOM, but there was no significant change between mean serum levels obtained pre- and postinitiation of antibiotic treatment in the time frame studied. The results suggest a systemic inflammatory response as evidenced by increased IL-6. A significant decrease of IL-6 and improvement of clinical symptoms were observed. Determining cytokine levels, especially IL-6, in AOM could offer a powerful tool for objective assessment of response to treatment, minimizing unnecessary treatment of asymptomatic children who may still have some otoscopic findings suggestive of AOM at follow-up visits.     

Serum cytokine detection in the clinical follow up of patients with cystic echinococcosis

The relation of serum cytokine levels and outcome of chemotherapy was evaluated in 15 patients with cystic echinococcosis. Serum IL-4, IL-10 and interferon-gamma (IFN-gamma) concentrations were determined by ELISA before and after a 3-month course of albendazole treatment: at least one serum sample per patient from 13 patients (87%) contained measurable amounts of IL-4; samples from five patients (33%) measurable amounts of IL-10 and samples from only two patients (13%) measurable amounts of IFN-gamma. Clinical assessment at 1 year after the end of therapy showed that 11 of the 15 patients had responded clinically. Seven of these patients had lower IL-4 serum concentrations, two had unchanged and two undetectable amounts (pre- versus post-therapy, n = 11, P = 0.008). Conversely, of the patients who did not respond, three had higher and one patient unchanged serum IL-4 concentrations. Serum IL-10 10 levels also decreased in all patients who responded (3/5) and increased in all patients who did not (2/5). No association was found between cytokine concentrations and cyst characteristics or antibody levels. Overall these data suggest that serum IL-4 detection may be useful in the follow up of patients with cystic echinococcosis.